Currently, there are many types of bone fillers and grafting biomaterials on the market approved for human implant use. Commercial examples include tricalcium phosphate, calcium sulfate, hydroxyapatite, and processed cadaveric allograft human bone grafts in large pieces, croutons and morsels, particles and powder forms intended for implant and surgical use. These products provide surrogate structural support in bone defect and musculoskeletal implant sites, and act as osteoconductive agents, or biomaterial scaffolds, to facilitate bone tissue regeneration, mechanical restoration of function, healing and structural re-integration of existing tissues. A second category of bone regenerative materials are called osteoinductive agents, usually in the form of small bioactive molecules and human purified recombinant growth factors (proteins) or extracted natural protein mixtures that stimulate or induce endogenous bone formation. Examples include Bone Morphogenetic Proteins (BMPs), statins, bioactive peptides (e.g., P15), and Demineralized Bone Matrix (DBM). These osteoinductive agents can be combined with osteoconductive biomaterials carriers in attempts to provide both benefits to patients.
Current clinically approved bone filler materials are problematic in patients because they are associated with several clinical problems, including lack of effective healing and tissue regeneration, lack of vascularity, insufficient structural and mechanical properties, and a high potential for developing infections at the surgical, trauma or implant site. Consequently, where bone loss is associated with an active infection or chronic lack of healing, currently available bone fillers are not recommended. The potential risk of introducing bone graft materials into an active infection, also at implant sites, requires a two-stage surgical procedure in which the infection is first eradicated, often requiring implant retrieval and resultant trauma, followed by implant replacement and subsequent bone grafting with autologous, synthetic, or allogenic graft materials.
Active infection at implant sites in and around bones and joints, in musculoskeletal trauma sites with or without implants, and in reducing open and closed fractures with and without fixation tooling, all remain problematic due to the prolonged systemic and/or local antibiotic treatments required for reliable resolution. Currently, when an infection is present, antibiotic is delivered to implant and trauma sites and bone defects through systemic drug infusions, through locally placed but temporary bone cement carriers, and direct topical use, all of which intend to deliver sufficient antibiotic dosing to the wound site. Antibiotic bone cement carriers placed locally into wound sites (e.g., cement beads containing antibiotics) allow the antibiotics to leach from the cement over a period of weeks. Much of the loaded drug dose is unable to leach from these solid, glassy matrices over extended times due to the dense delivery matrix and lack of ready drug transport within these carriers. Additionally, typical non-degrading or thermosetting cement-loaded matrices intended to resolve wound and implant infections require two surgical operations: one for placing the cement-drug matrix into the wound site, and a second for removal of the cement after drug dose exhaustion. Presently, no commercially available permanently implanted bone fillers or synthetic or allografted bone substitutes are able to incorporate an integrated drug, growth factor, antibiotic or combination agent release scheme.
Current techniques of delivering drugs, growth factors, and antibiotics locally into an active implant or bone infection site include the simple topical application of drug solutions, use of a drug-soaked collagen membrane or sponge, and use of polymer bone cement loaded with antibiotic drugs, usually as a soluble drug solution or solid drug powder dispersion, directly to the wound site. Numerous studies examining the drug leaching or elution properties of bone cement have demonstrated that the greatest concentration of drug release occurs within the first 8-10 days (so-called burst effect) followed by a reduced dose, with tapering release often too low to produce reliable therapy. Intravenous antibiotics are delivered to patients with bone and implant infections for an average of 6 to 8 weeks. Therefore, it is beneficial to have a local source of antibiotic release at these sites above the microbial killing threshold (e.g., minimal inhibitory concentration) and within the infection site for a similar time of 6 weeks, to reliably clear such infections from the implant and surrounding tissue sources of re-seeded infection.
Another problem that occurs in both orthopedic and dental surgery, as well as trauma and implant placement, is the occurrence of infection when bone grafting is used to fill bone defects. Typically, the rate of infection is greater when a bone graft is used than when it is not used, and with implants compared to no implants. Bone graft substitutes do not have or rapidly encourage an active host blood supply and cannot be adequately perfused by host defense components (cells and antibodies) and serum-circulating antibiotics. This “dead tissue” surrogate, while acting as a filler in the wound or defect site, can also serve as a perfect site for colonization, allowing infection to occur and persist.
Thus, needed are bone graft substitutes and fillers with antimicrobial properties that can incorporate and release multiple drug types in programmed ways to wound and surgical sites: antimicrobial agents alone or in tandem with osteoinductive agents or other pharmacologically active substances to produce effective tissue generation with osteoinducing agents plus microcidal antibiotic concentrations at the local site for extended time periods (6-8 weeks), affecting both opportunistic pathogens known to colonize wound and implant sites, those already present, and those that persist despite systemic therapy.